This work is conducted under protocol 89-M-0006 (NCT00001246), and falls into two broad research themes: Theme 1: Studies of behavior and brain organization in typically-developing groups Recruitment During the last year, we completed phase 1 of a Bring Back Project which recruited individuals who had previously been studied during childhood by the Child Psychiatry Branch an average of 20 years ago. This project represents the longest known neuroimaging follow-up study of human brain development, and provides a unique opportunity to study how childhood brain organization relates to later outcomes in adulthood. We have seen a total of 170 individuals in phase 1, and are currently preparing to invite participants back for a second visit. Published Research Findings We have published two collaborative studies which harness the precious longitudinal neuroimaging data gathered by the Child Psychiatry Branch over the past 20 years. These studies were made possible by data sharing and pooling between our laboratory and three others engaged in similar longitudinal neuroimaging studies of brain development in health. By resolving patterns of global and regional brain development between childhood and adulthood that are replicable across four independent groups, our findings set a new bar of consistency and replicability in developmental neuroimaging research. To present state-of-the art approaches to studying neuroanatomy using Magnetic Resonance Imaging (MRI), we also combined seminal results from the Child Psychiatry Branch longitudinal neuroimaging project in a cross-laboratory review paper in Nature Neuroscience. Theme 2: Deep phenotypic studies of participants with sex chromosome aneuploidy syndromes (SCAs) Recruitment During the last year, we completed a deep phenotyping study of individuals with XYY syndrome along with matched typically-developing controls. We have seen 65 individuals with XYY along with their family members, making this globally unique cohort the largest known group of XYY individuals with such comprehensive deep phenotypic data. A second clinical recruitment focus has involved collection of skin biopsies across individuals from nine different sex chromosome dosage groups, which are currently being profiled at several different genomic levels. These two projects represent the opening phase of an ongoing SCA study which will eventually include multiple other X and Y chromosome variations (e.g., XXY, XXX, etc.). Collectively, these studies are designed to expand on past work in SCA by gathering more comprehensive measures of brain structure and function, as well as providing more fine-grained information regarding the cognitive and behavioral variations that can be seen in SCA. These data will ultimately help to better define the developmental risks and resiliencies associated with X- and Y-chromosome dosage variation in humans, and identify neurobiological systems that might underpin these associations. We hope these insights will (i) improve accurate public and professional awareness of SCAs, (ii) help clinicians provide more targeted assessment and counseling to patient and families with SCA, and (iii) begin to identify biological markers with the potential to ultimately improve assessment, prediction and treatment of neurodevelopmental issues in SCA. More broadly, this work in the specific case of SCA will shed light on (i) the principles that organize genetic influences on brain and behavior in the context of neuropsychiatric impairment, and (ii) sex chromosome contributions to sex-differences in the brain, which are relevant for understanding the well-documented male-bias in risk for neurodevelopmental disorders more generally. Published Research Findings We have published two studies using existing neuroimaging data from an earlier phase of SCA research within the Child Psychiatry Branch. These data provide measures of brain anatomy across multiple different SCA groups and individuals without a SCA. Our studies have identified a set of brain regions that appear to be especially sensitive to SCA in terms of their anatomical development and represent promising new candidates in the search for neural systems that underpin some of the cognitive and behavioral changes that can be associated with SCA. In particular, we have focused this last year on clarifying SCA effects on folding of the cerebral cortex and regional anatomy of the cerebellum. Because SCAs exert a powerful effect on total brain volume, these focused studies have also required us to develop new statistical methods for proper control of total brain size effects when studying regional brain anatomy. These methods will be broadly useful to all researchers comparing groups that differ in total brain size and therefore have a large impact beyond the field of SCA.